Two separate effects contribute to regulatory T cell defect in systemic lupus erythematosus patients and their unaffected relatives

Forkhead box P3 (FoxP3)(+) regulatory T cells (T-regs) are functionally deficient in systemic lupus erythematosus (SLE), characterized by reduced surface CD25 [the interleukin (IL)-2 receptor alpha chain]. Low-dose IL-2 therapy is a promising current approach to correct this defect. To elucidate the origins of the SLE T-reg phenotype, we studied its role through developmentally defined regulatory T cell (T-reg) subsets in 45 SLE patients, 103 SLE-unaffected first-degree relatives and 61 unrelated healthy control subjects, and genetic association with the CD25-encoding IL2RA locus. We identified two separate, uncorrelated effects contributing to T-reg CD25. (1) SLE patients and unaffected relatives remarkably shared CD25 reduction versus controls, particularly in the developmentally earliest CD4(+)FoxP3(+)CD45RO(-)CD31(+) recent thymic emigrant T-regs. This first component effect influenced the proportions of circulating CD4(+)FoxP3(high)CD45RO(+) activated T-regs. (2) In contrast, patients and unaffected relatives differed sharply in their activated T-reg CD25 state: while relatives as control subjects up-regulated CD25 strongly in these cells during differentiation from naive T-regs, SLE patients specifically failed to do so. This CD25 up-regulation depended upon IL2RA genetic variation and was related functionally to the proliferation of activated T-regs, but not to their circulating numbers. Both effects were found related to T cell IL-2 production. Our results point to (1) a heritable, intrathymic mechanism responsible for reduced CD25 on early T-regs and decreased activation capacity in an extended risk population, which can be compensated by (2) functionally independent CD25 up-regulation upon peripheral T-reg activation that is selectively deficient in patients. We expect that T-reg-directed therapies can be monitored more effectively when taking this distinction into account.